Feuerbach Dominik, Schindler Patrick, Barske Carmen, Joller Stefanie, Beng-Louka Edwige, Worringer Katie A, Kommineni Sravya, Kaykas Ajamete, Ho Daniel J, Ye Chaoyang, Welzenbach Karl, Elain Gaelle, Klein Laurent, Brzak Irena, Mir Anis K, Farady Christopher J, Aichholz Reiner, Popp Simone, George Nathalie, Neumann Ulf
Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Biologics Center, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Neurosci Lett. 2017 Nov 1;660:109-114. doi: 10.1016/j.neulet.2017.09.034. Epub 2017 Sep 18.
Triggering receptor expressed in myeloid cells (TREM2) is a member of the immunoglobulin superfamily and is expressed in macrophages, dendritic cells, microglia, and osteoclasts. TREM2 plays a role in phagocytosis, regulates release of cytokine, contributes to microglia maintenance, and its ectodomain is shed from the cell surface. Here, the question was addressed at which position sheddases cleave TREM2 and what are the proteases involved in this process. Using both pharmacological and genetic approaches we report that the main protease contributing to the release of TREM2 ectodomain is ADAM17, (a disintegrin and metalloproteinase domain containing protein, also called TACE, TNFα converting enzyme) while ADAM10 plays a minor role. Complementary biochemical experiments reveal that cleavage occurs between histidine 157 and serine 158. Shedding is not altered for the R47H-mutated TREM2 protein that confers an increased risk for the development of Alzheimers disease. These findings reveal a link between shedding of TREM2 and its regulation during inflammatory conditions or chronic neurodegenerative disease like AD in which activity or expression of sheddases might be altered.
髓系细胞表达的触发受体（TREM2）是免疫球蛋白超家族的成员，在巨噬细胞、树突状细胞、小胶质细胞和破骨细胞中表达。TREM2在吞噬作用中发挥作用，调节细胞因子的释放，有助于小胶质细胞的维持，其胞外结构域从细胞表面脱落。在此，研究了金属蛋白酶在哪个位置切割TREM2以及参与该过程的蛋白酶有哪些。通过药理学和遗传学方法，我们报告说，促成TREM2胞外结构域释放的主要蛋白酶是ADAM17（一种含去整合素和金属蛋白酶结构域的蛋白质，也称为TACE，肿瘤坏死因子α转换酶），而ADAM10起次要作用。补充生化实验表明，切割发生在组氨酸157和丝氨酸158之间。对于R47H突变的TREM2蛋白，其脱落情况未改变，该突变蛋白会增加患阿尔茨海默病的风险。这些发现揭示了TREM2的脱落与其在炎症状态或慢性神经退行性疾病（如AD）中的调节之间的联系，在这些疾病中，金属蛋白酶的活性或表达可能会发生改变。
